Melanoma remains a large burden in the United States due to both its rising incidence and the lack of success in preventing melanoma-related death in people diagnosed with more advanced disease. It is a unique tumor in humans for its ability to elicit profound immune responses and for its sensitivity to treatments that target the immune system. As such, melanoma represents the ideal tumor for research in cancer immunology, particularly for studying the mechanisms by which tumors usurp the effector immune system and avoid current therapies. Recently, myeloid-derived suppressor cells (so-called MDSCs) have been implicated as key contributors in immune evasion by tumor cells. These cells suppress immune responses to cancer and limit the benefits of certain cancer treatments, such as cancer vaccines and immunotherapy. Currently available immunotherapies, such as anti-CTLA-4 (ipilimumab), could potentially be improved by reducing the frequency or activity of MDSCs. We propose that treatment with all-trans retinoic acid (ATRA), a derivative of vitamin A known to differentiate suppressive MDSCs into stimulatory dendritic cells, will decrease immunosuppression thereby increasing tumor-specific immunity. We hypothesize that combined treatment with ATRA and ipilimumab will 1) be safe and tolerable, 2) reduce the frequency and/or function of MDSCs in advanced-stage melanoma patients, and 3) increase the frequency and/or activation of tumor-specific T cell responses. This combined treatment tests the paradigm that overall response rates will be improved by simultaneously targeting effector cells and suppressor cells. Furthermore, by specifically targeting immunosuppressive MDSCs, this will be the first study to evaluate whether a reduction in MDSCs positively impacts disease progression in human melanoma patients. The aims of our proposal will test these hypotheses using the following methods: In aim 1, we will follow standard treatment protocols for ipilimumab to monitor patients with and without ATRA for adverse events. In aim 2, we will monitor the frequency and function of MDSCs in the peripheral blood throughout the course of treatment using flow cytometry and T cell suppression assays. In aim 3, we will use flow cytometry and T cell stimulation assays to monitor the frequency of T cell subsets, expression of activation markers, and tumor-specific T cell responses throughout the course of treatment. We will also monitor clinical disease progression and overall survival of treated patients. In summary, this innovative pilot study will determine if combinatorial treatment with ATRA and ipilimumab is safe and potentially effective for the treatment of Stage IV melanoma patients.